(2) Kandel’s Big Discovery

Eric Kandel (1929-) (lab site) won the Nobel prize in 2000 for cracking the memory code. Memory was a “black box” when Kandel began his research in the 1950s. Behaviorists such as B.F. Skinner, following Pavlov’s experiments with dogs, studied memory indirectly, by observing animal behavior. But no one before Kandel ventured inside the brain and figured out what was happening on a cellular and chemical level. From about 1965 to 1985, through dozens of scientific papers, Kandel effectively cracked the code.

Kandel’s big eureka moment occurred in the early 1960s when he decided to repeat Pavlov’s dog experiments on sea snails. Aplysia snails happen to have extra-large neurons which can be manipulated easily. Instead of teaching the snails with Pavlov’s bells and other sensory cues, Kandel stimulated the snails’ sensory neurons directly with electrodes. By a process of elimination, neuron by neuron, he mapped out the entire neural circuit of a simple behavior in the snails (the gill-withdrawal reflex) that changes and learns in response to its environment. Then, by removing parts of the circuit to a petri dish and subjecting the neurons to electric shocks and different chemicals, he determined many of the chemical pathways that mediate memory formation.

Pavlov's dog


Kandel's Aplysia

It should be noted that prior to Kandel’s discovery, scientists knew that some kind of chemical change must occur between neurons when we learn. Neurons themselves can’t change much—they are insulated fibers which are basically fixed in place according to our DNA. However, the connections between neurons are very flexible. There are small gaps between neurons called synapses across which neurons communicate by pumping out chemical messengers called neurotransmitters. Kandel found that neurons constantly adjust these neurotransmitters and, as Kandel dramatically discovered, sprout entirely new synaptic terminals, according to the rate of impulses passing through the neuron. Kandel wrote:

The growth and maintenance of new synaptic terminals makes memory persist. Thus, if you remember anything of this book, it will be because your brain is slightly different after you have finished reading it.Kandel discovered the chemical sequences for both short-term and long-term memory. In short-term memory, the neuron does not grow new synaptic terminals but adjusts the amount of neurotransmitters:

neurotransmitter -->cAMP-->kinases-->potassium-->calcium-->neurotransmitter

In long-term memory, new synaptic terminals appear—this only happens when neurotransmitters are pumped in high concentrations repeatedly, so that their chemical byproducts reach the nucleus of the cell and activate DNA, which encodes proteins needed to build new synaptic terminals:

neurotransmitter-->cAMP-->kinases-->CREB-->DNA-->mRNA+CPEB-->proteins

Kandel went on to perform experiments in the hippocampus of mouse brains, where he found an similar chemical sequence as found in snails. In the mouse, he found that the sequence correlated with a much more complex form of memory than he had found in snails—memory of the spatial layout of a room—which closely resembled human memory. Kandel also found that both age-related and Alzheimer’s memory loss in mice (as in humans) involve breakdowns in the sequence which could be offset by drugs. He also found that deficiencies in the sequence in other parts of the mouse brain (amygdala, striatum) are major contributors to other mental disorders such as anxiety disorders and schizophrenia.
Kandel found an interesting variation of the chemical sequence for memory formation in the mouse hippocampus:

neurotransmitter-->NMDA-->calcium-->AMPA-->glutamate

This sequence is affected by firing of different neurons converging on a third neuron—this creates a logical circuit called a “coincidence detector.” In humans, there are several other variations of the basic sequence discovered by Kandel which allow for different functions of neural computation. The general rule is that “cells that fire together, wire together.” This is the essence of associative learning.